Researchers at Johns Hopkins University and the University of Maryland School of Pharmacy have developed a series of novel first-in-class drugs that inhibit hypoxia-inducible factors 1 and 2, a pair of transcription factors considered “master regulators” of cancer progression. The study is scheduled to be published in the journal April 2nd. experimental medicine journal (gem) have shown that these drugs, when combined with immunotherapy, can completely eliminate breast, colorectal, melanoma, and prostate tumors in mice, suggesting that these drugs may ultimately be used to treat a wide range of cancers in humans.
Hypoxia-inducible factors 1 and 2 (HIF-1/2) are known as master regulators of cancer progression, as they control the activity of hundreds of genes important for cancer cell survival, proliferation, and spread (metastasis). Among other functions, HIF-1/2 promotes the formation of new blood vessels to nourish tumors and increase the ability of tumor cells to invade surrounding tissues. It also suppresses the ability of immune cells to attack tumors, limiting the effectiveness of immunotherapies such as immune checkpoint inhibitors.
HIF-1/2 levels increase in response to low oxygen levels (hypoxia), which are common in the core of rapidly growing tumors. The presence of hypoxia and elevated HIF-1/2 levels are important predictors of treatment failure and poor patient survival in a wide range of cancers. Belzutifan, a specific inhibitor of HIF-2, has been approved for use in the treatment of several cancers, including advanced renal cell carcinoma. However, because HIF-1 and HIF-2 have different roles in promoting cancer progression, drugs that target both transcription factors simultaneously may be more effective.
Dual HIF-1/2 inhibition presents a promising therapeutic strategy, especially for cancer types known to be prone to intratumoral hypoxia and resistant to conventional treatments. ”
Greg L. Semenza, co-senior author of new book gem Researcher and Professor at Johns Hopkins University School of Medicine
Semenza and colleagues worked with Professor Alexander D. Mackerel’s group at the University of Maryland School of Pharmacy’s Center for Computer-Aided Drug Design to identify drug molecules that can bind to both HIF-1 and HIF-2. SILCS, a computer-aided drug design technique, was used to predict small molecules that might bind to HIF-2 based on its known crystal structure. “The SILCS approach enabled the selection of compounds with a high probability of binding to HIF-2, allowing experimental efforts to focus on testing hundreds of compounds instead of millions, thereby accelerating the drug discovery process,” Mackerel says.
Semenza’s team, including lead author Dr. Shaima Salman, tested these candidate molecules and identified several compounds that bind to both HIF-1 and HIF-2, causing their degradation and preventing activation of target genes. “These compounds showed broad and potent HIF-inhibiting activity in a variety of cancer cell lines,” Salman says.
Individual drugs were able to inhibit the growth of breast, colorectal, head and neck, melanoma, and prostate tumors, reduce tumor angiogenesis, and limit tumor invasion in mice.
These drugs were even more effective when combined with the immune checkpoint inhibitors anti-CTLA-4 or anti-PD1. The combination therapy resulted in complete remissions in more than 50% of mice with breast, colorectal, melanoma, or prostate tumors, many of which were resistant to treatment with immune checkpoint inhibitors alone. These animals remained tumor-free even when rechallenged with fresh tumor cells.
Semenza et al. found that dual HIF-1/2 inhibitors change the types of immune cells found within tumors, decreasing the types of immunosuppressive cells while increasing the frequency of T cells and NK cells, which are capable of killing tumor cells, especially when treated with immune checkpoint inhibitors.
“We observed increased responses to HIF inhibitor treatment and immune checkpoint inhibitors in a wide range of cancer samples, suggesting that this combination has broad clinical utility,” Professor Semenza said. In addition to the therapeutic potential of these drugs, the researchers note that their dual HIF-1/2 inhibitors can be administered orally and have shown no safety concerns in mice, even when administered at doses well above the effective dose for long periods of time.
sauce:
Rockefeller University Press
Reference magazines:
Salman, S. and others. (2026) Targeting conserved domains of hypoxia-inducible factors for cancer therapy. experimental medicine journal. DOI: 10.1084/jem.20251009.
